A-nor-cholestatriene-21-oic acid 21-&gt;24 lactones



Patented Aug. 15, 1967 United States Patent "fee 3336338 beginning with compounds of the following formulae as 3,336,338 starting material:

A-NOR-CHOLESTATRIENE-2I-OIC ACID 21-)24 LACTONES David Walter Rosenthal, New Brunswick, and [Iosef Fried, 5 Y

Princet0n,.N.J., assignors, by mesne assignments, to E; R. Squibb 8: Sons, Inc., New York, N-Y., a corporation of Delaware 0 O No Drawing. Filed Sept. 13, 1963, Ser.'No. 308,664 0: 0:

- 2 Claims. (Cl. 2,60-343.5) s

10 This invention relates to and has for-its objectives the provision of physiologically active steroids, methods for preparing the same and new intermediates useful in said I I preparation. 6 (13H! The final products of this invention can be represented I by the formulae 1 R'O 7 me on! CHzOR CHaOR s a g g 0R v j i I v o; Bv l OJ O l g g and r CH8 CHEOR /RI! v i I wherein R may be hydrogen or acyl, R" is hydrogen; R' R is hydroxy or acyloxy, and together R and R is oxo o 40 (0:)

7 Among the starting materials which may be employed in the practice of this invention are those which may be prepared according to the procedures set forth in our wherein R is hydrogen or acyl; R" is hydrogen; R' is Impending pp c 5311 filed y 24, hydroxy or aoyloxy and together R and R" is oxo 2, W Patent 3 0 9, granted Pal 1965,

and Ser. No. 183,014, filed-Mar. 28, 1962, now Patent The compounds of this invention are physiologically N 3, g 9 and'whicl} in active steroids 'which possess anti-androgenic activity and 1S a oontlmlatwn-m-paft of our F appllcatlon,

thus' can be employed in the treatment of such conditions NOJ 32, 9, filtid gnow abandoned, and as hyperandrogenic acne. The compounds may be formucopelldmg f pp filed on n lated for such administration, the concentration and/or date herewith, now Patent No. 3,271,390, granted Sept.

"dosage being based on the activity of the particular com '6, 1966, in 1116' e of Josef Fried. The compounds pound in the requirements of the ati t, Y which may be employed as starting materials mclude 3B- The preferred acyl radicals are those of hydrocarbon Y- y Y- 21 c a carboxylic acids of less than 12 carbon atoms, as exemplilactolle. Py e),'3/3,16u di'ac etoxy 24 hydroxyfied by the lower alkanoic acids (e.g., acetic, propionic, -1 a r 21 9 acid q 1 3- butyric and tert.-pentanoic acids), the lower alkenoic .dro ya 1 1 o id e e, acids, the monocyclic aryl earboxylic acids (e.g., benzoic 3B,16a,24 trihydroxy-A -lanostatr1ene-2l-oic acid and toluic acids), the monocyclic aryl lower alkanoic lae one, 35,15 1 (1iECC'EOXY-Z4-hYdI'OXY-A -1a1105t3.- acids (e.g., phenacetic and p-phenylpropionic acids), the triene-21-oic acid lactone, 3,3,15a,24-tr1hydroxy-A cycloalkane carboxylic and the cycloalkene ca-rboxylic anos trie -flc 861d flxy-24-hydroxy- .acids. 15-keto- A 2 lanostatriene21-oic acid lactone.

The final products of this invention are prepared by the The steps of the process of this invention are generally process of this invention which entails a number of steps represented by the following equatlons wherein R repre- 3 sents hydrogen or acyl; and Z represents COOH, COCH or CH OH:

CHrOR I Z=COOH IV R=H II Z=COOCH3 V R=COCHa III Z=CH2OH In the first step of the process of this invention, the 3B-hydroxy-A -starting materials (Compounds A) enumerated hereinabove are reacted with phosphorous pentachloride to yield the 3-isopropylidene A-nor-A -derivatives (Compounds B) which are new compounds of this invention.

Compounds B are then reduced as by treatment with a reducing agent such as lithium aluminum hydride, for an extended period of time, to yield the 3-is0propylidene- A-nor-A -21-alkanol derivatives (Compounds C), which are also new compounds of this invention. To obtain the 3-isopropylidene-A-nor-M-Z1-oic acid derivatives (Compounds C, wherein Z=COOH) which are also new compounds of this invention, the reduction is allowed to proceed for only a short time.

Compounds C are then ozonized as by treatment with ozone, to yield the 21-hydroxy-A-nor-A -pregnene-3,20- dione (Com-pounds D) which are the final compounds of this invention.

The invention may be finther illustrated by the following examples:

EXAMPLE 1 3,8,24-dihydroxy-A -lan'ostatriene 2l-oic acid 21 24-lwctone (A) 3/3 acetoxy-24-hydroxy-A -lanostat1iene-2l-oic acid 21- 24-lactone (250 mg.) is suspended in 125 ml. methanol 0.7 M in KOH. The suspension is shaken at room temperature for fifteen hours. The product contains large prisms which are filtered off and crystallized from ethyl acetate to yield 35 mg. of pure pyrone-S-ol (A) (M.P. 262264). The filtrate is neutralized carefully to pH 7.2 with dilute sulfuric acid and concentrated. The concentrate is combined with the mother liquors from the first crystals and extracted with chloroform. The organic layer is washed with water, then dried over sodium sulfate and evaporated. Crystallization from acetone and from ethyl acetate gives several crops, which are 4 combined to give 138 mg. of pure 35,24-dihydroxy- A -lanostatriene-2l-oic acid 21- 24-lactone (A), M.P. 262264; [a] 146 (c., 0.76 in CHCl Analysis.-Calcd. for C H O C, 79.60; H, 9.80. Found: C, 79.50; H, 9.83.

EXAMPLE 2 3-isopr0pylidene-24-hydroxy-14-methyl-A -A-narcholestatriene-ZI-oic acid 21 24-lactonc (B) To a suspension of 3fl,24-dihydroxy-A -lanostatriene-21-oic acid 21 24-lactone (A) (104 mg.) in 50 ml. of toluene which is cooled to 0-5 with ice, 108 mg. of phosphorus pentachloride is added and the flask covered with a dark cloth. Helium is then bubbled through the magnetically stirred solution as fast as it can be contained in the flask. Hydrochloric acid fumes are seen for the first five minutes in the efiiuent gas. The reaction is quenched after twelve minutes with excess 10% potassium carbonate solution and the organic phase is extracted three more times with this reagent. The organic phase is finally washed with saturated sodium chloride solution,

7, dried over sodium sulfate, filtered and evaporated. Beautiful, fine needles of 3-isopropy1idene-24-hydroxy-14- methyl-A -A-norcholestatriene-2l-oic acid 21 24- lactone (B) separated from absolute ethanol yielding 78 mg, M.P. 182-185; [u] -165 (c., 0.51 in CHCl Mills. 305 u (e=10,300)

A221 5.78, 6.10, 6.33 and 9.080

Analysis.-Calcd. for C H O C, 82.90; H, 9.74. Found: C, 83.20; H, 9.49.

EXAMPLE 3 3-isopropylidene-21-hydr0xy-I4-methyl-A -A-n0rcholestatriene (C; III) A solution of 3-isopropylidene-24-hydroxy-14-methyl- I; M A nor cholestatriene 21- 24-lactone (B) (M.P. 182-183") in 5 ml. of freshly distilled tetrahydrofuran is added dropwise to a refluxing stirred suspension of lithium aluminum hydride in tetrahydrofuran over a five-minute period. The reaction is carried out under I: nitrogen. The reaction mixture is then heated under reflux for an additional hour and cooled and decomposed with ca. 1 ml. of saturated sodium sulfate solution. The resulting precipitate is filtered off and washed three times with benzene. The combined filtrates are dried over sodium sulfate and evaporated to give 102 mg. of a clear oil possessing 21%.. 243 u iam.

max.

[a] -|-48 (c., 1.43 in CHCI Compound (C: III) when crystallized from methanol forms a solvent (M.P. 78-80") which on melting decomposes and reforms into crystals .and melts again at -116. Alternatively, the higher melting point can be obtained directly by drying in high vacuum at ca. 50.

Analysis.-Calcd. for C H O: C, 85.24; H, 10.97. Found: C, 85.32; H, 10.89. v

5 EXAMPLE 4 3-is0pr0pylidene-1 4-methy Z-A -A -nrch0 lestatriene-21-0ic acid (C; I)

A solution of 3-isopropylidene-24-hydroxy-l4-methyl- M -A-norcholestatriene-2l-oic acid 21- 24-lactone (B) (106 mg.) in 2 ml. of tetrahydrofuran is added rapidly to a solution of 103 mg. of lithium aluminum hydride in 2 ml. of tetrahydrofuran. The mixture is refluxed for an additional three minutes, cooled to room temperature and Worked up with saturated sodium sulfate solution and benzene, filtered and evaporated to dryness. The residue is chromatographed on five grams of activity V, Woelm neutral alumina and the major fraction is eluted with methanol in chloroform yielding 55 mg. of semicrystalline material melting at l65l70. Two crystallizations furnishes pure 3-isopropylidene-l4-methyl-A-norcholestatriene-Zl-oic acid (C; I) of the following properties: M.P. 169-170"; [oc] +86 (c., 0.75 in CHClg);

was. 252 my (e=17,300)

Anulol mm 3.85, 5.94, 5.98, 6.23 and 10.24;].

Analysis.-Calcd. for C H O C, 82.51; H, 10.16. Found: C, 82.29; H, 9.88.

EXAMPLE 5 Methyl 3-isopr0pylidene-14-methyl-A -A-norch olesta triene-ZI -0ate 3-isopropylidene-14 methyl-A -A-norcholestatriene-Zl-oic acid is reacted with idiazomethane in methanol-ether to yield methyl 3-isopropylidene-l4-methyl- M -A-norcholestatriene-2l-oate. After recrystallization from methanol the product has the following properties: M.P. l26l28;

A3}; 254 mp (e=17,700) [a] +7 (c., 1.04 in CHCl Affii} 5.86, 5.09, 6.21, 8.29, 10.19;;

Analysis.Calcd. for C H O C, 82.61; H, 10.29. Found: C, 82.76; H, 10.39.

EXAMPLE 6 3-is0propylidene-21 -hydroxy-1 4-methyl-A -A norcholestatriene EXAMPLE 7 A solution of 100 mg. of pure 3-isopropylidene-21-hydroxy-14-methyl-A -A-norcholestatriene (C, III) in ml. of methylene chloride containing 50 mg. of pyridine (2.7 M equivalents) is cooled to 60 and ozonized with a stream containing 1.29 mmoles per liter of gas. The breakthrough in the K1 trap following the ozonizing vessel occurs at 3 milliequivalents of ozone.

The crude product is decomposed with zinc dust and a few drops of glacial acetic acid. The test for peroxide is negative after 30 minutes and the organic phase is filtered and washed with water and saturated with sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation of the solvent, the residual product mg.) is dissolved in 2 m1. of pyridine containing 0.5 ml. of acetic anhydride and allowed to stand at room temperature overnight. The oil resulting on evaporation of the reagents is subjected to thin layer chromatography on silica gel and on acid washed alumina (activity V). In addition to numerous tetrazolium-negative spots, one tetrazolium-positive area moving slightly faster than DOCA with 1:3 chloroform-benzene is observed. On elution 7 mg. are isolated (M.P. -470") which have an IR spectrum and mobility essentially identical with those of authentic 2l-acetoxy-l4-methyl-A -A-nor-SB- regnene- 3,20-dione prepared by the route described in our copending application Ser. No. 288,920, filed June 19, 1963.

EXAMPLE 8 Treating the 16-acetoxy or l6-hydroxy starting materials in accordance with the procedure set forth in Examples 1 through 7 yields the corresponding l6-substituted derivative of the compounds of those examples.

EXAMPLE 9 Similarly, treating the lS-acetoxy or 15-hydroxy starting materials in accordance with the procedure set forth in Examples 1 through 7 yields the corresponding 15- substituted derivative of the compounds of those examples.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound having the formula wherein R is selected from the group consisting of hydrogen and acyl; R" is hydrogen; R' is selected from the group consisting of hydrogen, hydroxy and acyloxy; wherein the acyl moiety in each instance is a hydrocarbon carboxylic acid of less than twelve carbons selected from the group consisting of lower alkanoic acids, lower alkenoic acids and monocyclic aryl carboxylic acids; and together R and R" is 0x0.

2. 3-isopropy1idene-24 hydroxy-l4-methyl-A A-norcholestatriene-Zl-oic acid 21 24-lactone.

No references cited.

ALEX MAZEL, Primary Examiner.

I. A. NARCAVAGE, Assistant Examiner. 

1. A COMPOUND HAVING THE FORMULA 